EP4514783A1 - Process for the preparation of [1,4,5]-oxadiazepine derivatives - Google Patents

Process for the preparation of [1,4,5]-oxadiazepine derivatives

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Publication number
EP4514783A1
EP4514783A1 EP23719404.8A EP23719404A EP4514783A1 EP 4514783 A1 EP4514783 A1 EP 4514783A1 EP 23719404 A EP23719404 A EP 23719404A EP 4514783 A1 EP4514783 A1 EP 4514783A1
Authority
EP
European Patent Office
Prior art keywords
process according
base
butanol
solvent
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23719404.8A
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German (de)
French (fr)
Inventor
Linhua Wang
Robert SARDZIK
Joseph Pike MITCHENER JR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Publication date
Application filed by Syngenta Crop Protection AG Switzerland filed Critical Syngenta Crop Protection AG Switzerland
Publication of EP4514783A1 publication Critical patent/EP4514783A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • C07D273/06—Seven-membered rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
    • B01D3/34—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping with one or more auxiliary substances
    • B01D3/36—Azeotropic distillation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0255—Phosphorus containing compounds
    • B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
    • B01J31/0268—Phosphonium compounds, i.e. phosphine with an additional hydrogen or carbon atom bonded to phosphorous so as to result in a formal positive charge on phosphorous
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for the preparation of [l,4,5]-oxadiazepines derivatives and their use as intermediates in the preparation of herbicides of the tetrahydropyrazolodione type.
  • Pinoxaden [8-(2,6-diethyl-4-methylphenyl)-7-oxo-l,2,4,5-tetrahydropyrazolo [1,2-d] [1,4,5] oxadiazepin-9-yl] 2,2-dimethylpropanoate
  • DADA diacetyloxadiazepine
  • DAODA is typically prepared from the reaction of diacetylhydrazine (DAH) and dichloroethyl ether (DCEE) in the presence of dimethyl sulphoxide (DMSO). This is described in WO 03/051853 Al.
  • the present invention therefore provides a process for the preparation of a compound of formula (I):
  • R 1 -C(O)-NH-NH-C(O)-R 2 with R 3 -CH 2 -CH 2 -O-CH 2 -CH 2 -R 4 , in the presence of an alcoholic solvent; wherein R 1 and R 2 are independently selected from straight or branched chain alkyl groups, or are bonded to form a 4, 5, or 6-membered heterocycle, and wherein R 3 and R 4 are independently selected from a halide or a sulphate.
  • the claimed process offers a significant advantage to the use of DMSO as it does not suffer from thermal instability leading to potential major accident hazard and can therefore be safely ran at a higher process concentration. It also avoids the combination of DCEE/DMSO which is highly toxic. Furthermore, the process enables the removal of a solvent swap from the process, as the process solvent may be used for both the reaction and the crystallisation of the product. Together with a reduction in inorganic and solvent waste, the process is more economical than those known in the art.
  • R 1 and R 2 are independently selected from a straight chain alkyl groups, preferably with a chain length of from 1 to 4 carbons, even more preferably selected from methyl or ethyl.
  • R 1 and R 2 may both be methyl.
  • R 1 and R 2 are bonded to form a 5-membered heterocycle derived from pyrazolidine (i.e., R 1 and R 2 represent the same CF moiety).
  • the ring may have one or more carbonyl groups.
  • the ring comprises two carbonyl groups to form a pyrazolidinedione derivative, even more preferably the carbonyl groups are in the 3 and 5 positions.
  • the ring may be substituted in any fashion, for instance the ring may have a phenyl substituent (e.g., at position 4), which in itself may be substituted.
  • R 3 and R 4 are independently selected from methyl sulfonyl (e.g., 2-(2- methylsulfonyloxyethoxy)ethyl methanesulfonate), chlorine and/or bromine; most preferably R 3 and R 4 are chlorine (DCEE).
  • methyl sulfonyl e.g., 2-(2- methylsulfonyloxyethoxy)ethyl methanesulfonate
  • chlorine and/or bromine most preferably R 3 and R 4 are chlorine (DCEE).
  • the alcoholic solvent may be a poly- or monohydric alcohol, preferably a monohydric alcohol.
  • the alcohol is a C1-7 alcohol (e.g. methanol), such as a C2-6 alcohol (e.g., ethanol).
  • the alcohols may be straight or branched chain alcohols.
  • the solvent is selected from butanol, pentanol (such as n-pentanol and/or isopentanol) or 2-methoxyethanol, preferably butanol (such as n-butanol).
  • n-butanol exhibits all of the criteria (1) to (5) above.
  • the process is carried out in the presence of a phase-transfer catalyst (PTC) in order to increase the speed of the reaction.
  • PTC phase-transfer catalyst
  • the PTC is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the PTC is a nucleophilic catalyst
  • it is preferably selected from l,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and/or 4-Dimethylaminopyridine (DMAP).
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • DBU quinuclidine
  • DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
  • DMAP 4-Dimethylaminopyridine
  • the PTC is an ammonium catalyst it preferably has the formula R a R b R c NX, where R a , R b and R c are independently selected from alkyl, substituted alkyl and phenyl groups and X is selected from halide, hydroxide or sulphate.
  • TMAC Tetramethylammonium chloride
  • TBAB Tetrabutylammonium bromide
  • ALIQUAT 336 N-Methyl-N,N,N-trioctylammonium chloride
  • TMA HCI Trimethylamine hydrochloride
  • the PTC is a phosphonium catalyst it preferably has the structure R a R b R c PX, where R a , R b and R c are independently selected from alkyl, substituted alkyl and phenyl groups, and X is selected from halide, hydroxide or sulphate.
  • MMTPPCI Metal Organic Triphenylphosphonium chloride
  • FMTPPCI Formylmethyltriphenylphosphonium chloride
  • BuTPPCI n-butyltriphenylphosphonium chloride
  • Benzyltriphenylphosphonium chloride Benzyltriphenylphosphonium chloride
  • TPPBr Tetraphenylphosphonium bromide
  • PrTPPBr n-propyltriphenylphosphonium bromide
  • TBPOH tetrabutylphosphonium hydroxide
  • THTDPCI Tetra(hydroxymethyl)phosphonium chloride
  • THMPCI Tetrabutylphosphonium bromide
  • TPP Triphenylphosphine
  • TPP Tributyltetradecylphosphonium chloride
  • TPCI Tetrabutylphosphonium chloride
  • the PTC is preferably l,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst, even more preferably l,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst selected from tributyltetradecylphosphonium chloride (TBTDPCI), tetrabutylphosphonium chloride (TBPCI) and/or tetrabutylphosphonium hydroxide (TBPOH).
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • a phosphonium catalyst selected from tributyltetradecylphosphonium chloride (TBTDPCI), tetrabutylphosphonium chloride (TBPCI) and/or tetrabutylphosphonium hydroxide (TBPOH).
  • the PTC is present in an amount of from 0.005 to 0.05 molar equivalent relative to R 1 - C(O)-NH-NH-C(O)-R 2 , preferably from 0.01 to 0.02 molar equivalents.
  • the base may be selected from potassium carbonate, sodium carbonate and caesium carbonate, but is preferably potassium carbonate.
  • the base is present in an amount of from 1.5 to 3.0 molar equivalents relative to R 1 -C(O)- NH-NH-C(O)-R 2 , preferably from 1.8 to 2.5 molar equivalents.
  • the process typically requires a high loading of base, which limits yields and produces a significant amount of solid waste.
  • the process is therefore preferably carried out in the presence of a base and a co-base in order to address these issues.
  • the co-base may be selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide and caesium hydroxide, preferably potassium hydroxide.
  • the ratio of base to co-base is from 10:1 to 1:2, preferably from 5:1 to 1:1.
  • the process comprises a reaction stage (1) as defined herein.
  • the reaction rate and yield are highly dependent on the pot temperature.
  • the reaction temperature can be controlled by running the reaction under reflux at one atmosphere pressure or under reduced pressure.
  • the reaction is preferably carried out at the solvent reflux temperature, preferably from 110 to 125 °C.
  • the process comprises a salt filtration stage (2) subsequent to the reaction stage, preferably comprising the addition of further alcoholic solvent as defined herein.
  • This stage may also comprise the removal of solid waste.
  • solvent distillation stage (3) where solvent can be recycled back to the reaction stage (1).
  • this can be the sole solvent distillation stage.
  • the process advantageously comprises a product crystallization stage (4).
  • Stages (3) and (4) are preferably combined as a single stage.
  • a filtration and drying (5) stage to isolate the compound of formula (I), advantageously comprising the addition of alcoholic solvent as defined herein to wash the product.
  • the reaction is sensitive to the water content and so the process preferably comprises the removal of water via azeotropic distillation.
  • the water content can be controlled by azeotropic distillation, this has been found to be particularly effective when a co-base (such as potassium hydroxide) is used.
  • a process for preparing pinoxaden comprising a process as defined herein.
  • Such a process may comprise the hydrolysis of a compound of formula (I) to form oxadiazepine (ODA).
  • ODA may be reacted with 2-(2,6-Diethyl-4- methylphenyl)malonamide in order to form a pinoxaden intermediate.
  • a compound of formula (I) produced by a process as defined in herein.
  • Such a compound is preferably used in a process for the preparation of pinoxaden.
  • DCEE (73.2 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (130.6 g) were fed sub-surface separately via syringe pumps.
  • DCEE and KOH solution were both fed over 4 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • DCEE (73.2 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (130.6 g) were fed sub-surface separately via syringe pumps.
  • DCEE and KOH solution were both fed over 4 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • DCEE 54.9 g, 1.5 eq
  • a solution of 14.5 w/w% KOH in n-butanol 78.6 g
  • DCEE and KOH solution were both fed over 4 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • DCEE 54.9 g, 1.5 eq
  • a solution of 14.5 w/w% KOH in n-butanol 78.4 g
  • DCEE and KOH solution were both fed over 4 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • DCEE 54.9 g, 1.5 eq
  • a solution of 14.5 w/w% KOH in n-butanol (78.4 g) were fed sub-surface separately via syringe pumps.
  • DCEE and KOH solution were both fed over 4 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • the inorganic solids (50.0 g) were removed via filtration at room temperature, which was followed by n-butanol wash (100 g).
  • the combined filtrate and wash (292.8 g) gave a solution yield of 55.5%. Concentration under reduced pressure at 55-60 °C rendered a concentrate (55.8 g) containing about 43.5% of DAODA.
  • DCEE (24.9 g, 1.7 eq) and a solution of 14.5 w/w% KOH in n- butanol (31.4 g) were fed sub-surface separately via syringe pumps.
  • DCEE was fed over 4 hours and KOH solution fed over 6 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 16-hour period. After reaction completion, the inorganic solids (25.4 g) were removed via filtration at room temperature followed by a n-butanol wash (30 g) at room temperature.
  • the combined filtrate and n- butanol wash (163.5 g) gave a solution yield of 60.4%.
  • DCEE 82.5 g, 1.7 eq
  • a solution of 14.5 w/w% KOH in n-butanol (103.9 g) were fed sub-surface separately via syringe pumps.
  • DCEE was fed over 4 hours and KOH solution fed over 6 hours.
  • the rate of water/solvent removal was adjusted to match the feed rate of base.
  • the reaction was sampled periodically over a 12-hour period.
  • the GC chemical yield for DAODA was 55.3%.

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Abstract

A process for the preparation of a compound of formula (I) comprising the reaction of: R1-C(O)-NH-NH-C(O)-R2, with R3-CH2-CH2-O-CH2-CH2-R4, in the presence of an alcoholic solvent; wherein R1 and R2 are independently selected from straight or branched chain alkyl groups, or are bonded to form a 4, 5, or 6-membered heterocycle, and wherein R3 and R4 are independently selected from a halide or a sulphate.

Description

PROCESS FOR THE PREPARATION OF [1,4,5]-OXADIAZEPINE DERIVATIVES
The present invention relates to a novel process for the preparation of [l,4,5]-oxadiazepines derivatives and their use as intermediates in the preparation of herbicides of the tetrahydropyrazolodione type.
Pinoxaden ([8-(2,6-diethyl-4-methylphenyl)-7-oxo-l,2,4,5-tetrahydropyrazolo [1,2-d] [1,4,5] oxadiazepin-9-yl] 2,2-dimethylpropanoate) is a well-known graminicidal herbicide. The current commercial process forthe preparation of pinoxaden involves the preparation of diacetyloxadiazepine (DAODA) as a key intermediate.
DAODA is typically prepared from the reaction of diacetylhydrazine (DAH) and dichloroethyl ether (DCEE) in the presence of dimethyl sulphoxide (DMSO). This is described in WO 03/051853 Al.
However, the use of DMSO has a significant number of technical problems associated with it. There are significant process safety issues due to the thermal decomposition of DMSO, low isolated yields, poor volume yields and a high number of waste streams. The process as a whole has a high level of complexity and cost due to the need for at least three distillation steps and difference solvents for the reaction and for crystallisation.
There is thus a need for a process that remedies the above technical problems.
The present invention therefore provides a process for the preparation of a compound of formula (I):
R1-C(O)-NH-NH-C(O)-R2, with R3-CH2-CH2-O-CH2-CH2-R4, in the presence of an alcoholic solvent; wherein R1 and R2 are independently selected from straight or branched chain alkyl groups, or are bonded to form a 4, 5, or 6-membered heterocycle, and wherein R3 and R4 are independently selected from a halide or a sulphate.
The claimed process offers a significant advantage to the use of DMSO as it does not suffer from thermal instability leading to potential major accident hazard and can therefore be safely ran at a higher process concentration. It also avoids the combination of DCEE/DMSO which is highly toxic. Furthermore, the process enables the removal of a solvent swap from the process, as the process solvent may be used for both the reaction and the crystallisation of the product. Together with a reduction in inorganic and solvent waste, the process is more economical than those known in the art.
Preferably, R1 and R2 are independently selected from a straight chain alkyl groups, preferably with a chain length of from 1 to 4 carbons, even more preferably selected from methyl or ethyl. R1 and R2 may both be methyl.
In an alternative preferred embodiment, R1 and R2 are bonded to form a 5-membered heterocycle derived from pyrazolidine (i.e., R1 and R2 represent the same CF moiety).
Optionally, the ring may have one or more carbonyl groups. Preferably the ring comprises two carbonyl groups to form a pyrazolidinedione derivative, even more preferably the carbonyl groups are in the 3 and 5 positions. The ring may be substituted in any fashion, for instance the ring may have a phenyl substituent (e.g., at position 4), which in itself may be substituted.
Preferably R3 and R4 are independently selected from methyl sulfonyl (e.g., 2-(2- methylsulfonyloxyethoxy)ethyl methanesulfonate), chlorine and/or bromine; most preferably R3 and R4 are chlorine (DCEE).
Solvent System
The alcoholic solvent may be a poly- or monohydric alcohol, preferably a monohydric alcohol. Advantageously, the alcohol is a C1-7 alcohol (e.g. methanol), such as a C2-6 alcohol (e.g., ethanol). The alcohols may be straight or branched chain alcohols. Most advantageously, the solvent is selected from butanol, pentanol (such as n-pentanol and/or isopentanol) or 2-methoxyethanol, preferably butanol (such as n-butanol).
The optimum solvent for the process described herein must:
1) be chemically compatible with the process (i.e., thermally stable);
2) have a high polarity for rate enhancement;
3) provide good solubility of the base and the DAH salt;
4) be immersible with water (which is advantageous as single solvent for reaction and crystallization); and
5) have an adequate boiling point in view of the reaction temperature of from 115 to 125 °C.
It was surprisingly found that n-butanol exhibits all of the criteria (1) to (5) above.
Phase Transfer Catalyst
Advantageously, the process is carried out in the presence of a phase-transfer catalyst (PTC) in order to increase the speed of the reaction.
Preferably the PTC is
1) a nucleophilic catalyst;
2) an ammonium catalyst; or
3) a phosphonium catalyst.
Where the PTC is a nucleophilic catalyst, it is preferably selected from l,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and/or 4-Dimethylaminopyridine (DMAP).
Where the PTC is an ammonium catalyst it preferably has the formula RaRbRcNX, where Ra, Rb and Rc are independently selected from alkyl, substituted alkyl and phenyl groups and X is selected from halide, hydroxide or sulphate.
More preferably it is selected from Tetramethylammonium chloride (TMAC), Tetrabutylammonium bromide (TBAB), N-Methyl-N,N,N-trioctylammonium chloride (ALIQUAT 336), Trimethylamine hydrochloride (TMA HCI) and/or 1,4,7,10,13,16-hexaoxacyclooctadecane (18-CROWN-6). Where the PTC is a phosphonium catalyst it preferably has the structure RaRbRcPX, where Ra, Rb and Rc are independently selected from alkyl, substituted alkyl and phenyl groups, and X is selected from halide, hydroxide or sulphate.
More preferably it is selected from (Methoxymethyl)triphenylphosphonium chloride (MMTPPCI), Formylmethyltriphenylphosphonium chloride (FMTPPCI), n-butyltriphenylphosphonium chloride (BuTPPCI), Benzyltriphenylphosphonium chloride (BenzylTPPCI), Tetraphenylphosphonium bromide (TPPBr), n-propyltriphenylphosphonium bromide (PrTPPBr), tetrabutylphosphonium hydroxide (TBPOH), tri(n-hexyl)tetradecylphosphonium chloride (THTDPCI), Tetra(hydroxymethyl)phosphonium chloride (THMPCI), Tetrabutylphosphonium bromide (TBPBr), Triphenylphosphine (TPP), Tributyltetradecylphosphonium chloride (TBTDPCI) and Tetrabutylphosphonium chloride (TBPCI).
The PTC is preferably l,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst, even more preferably l,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst selected from tributyltetradecylphosphonium chloride (TBTDPCI), tetrabutylphosphonium chloride (TBPCI) and/or tetrabutylphosphonium hydroxide (TBPOH).
These catalysts have been found to improve both rate and yield, as well as being stable at the relevant reaction temperatures.
Advantageously the PTC is present in an amount of from 0.005 to 0.05 molar equivalent relative to R1- C(O)-NH-NH-C(O)-R2, preferably from 0.01 to 0.02 molar equivalents.
Base System
It has been found that the presence and identity of a base plays a significant role in the optimisation of the process. Thus, advantageously, the process is carried out in the presence of a base. The base may be selected from potassium carbonate, sodium carbonate and caesium carbonate, but is preferably potassium carbonate.
Preferably the base is present in an amount of from 1.5 to 3.0 molar equivalents relative to R1-C(O)- NH-NH-C(O)-R2, preferably from 1.8 to 2.5 molar equivalents. However, the process typically requires a high loading of base, which limits yields and produces a significant amount of solid waste. The process is therefore preferably carried out in the presence of a base and a co-base in order to address these issues. The co-base may be selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide and caesium hydroxide, preferably potassium hydroxide.
Advantageously, the ratio of base to co-base is from 10:1 to 1:2, preferably from 5:1 to 1:1.
Process Stages
The process comprises a reaction stage (1) as defined herein. The reaction rate and yield are highly dependent on the pot temperature. Advantageously, the reaction temperature can be controlled by running the reaction under reflux at one atmosphere pressure or under reduced pressure. The reaction is preferably carried out at the solvent reflux temperature, preferably from 110 to 125 °C.
Advantageously, the process comprises a salt filtration stage (2) subsequent to the reaction stage, preferably comprising the addition of further alcoholic solvent as defined herein. This stage may also comprise the removal of solid waste.
Preferably, there is a solvent distillation stage (3), where solvent can be recycled back to the reaction stage (1). Advantageously, but not necessarily, this can be the sole solvent distillation stage.
Alternatively, there is a second distillation stage after product filtration to recover residual solvent and excess R3-CH2-CH2-O-CH2-CH2-R4. The mother liquor contains the PTC and a significant amount of the reagents. The mother liquor can therefore replace part of solvent in the next reaction batch leading to an increased yield and reduced usage of reagents.
The process advantageously comprises a product crystallization stage (4). Stages (3) and (4) are preferably combined as a single stage.
Preferably, there is a filtration and drying (5) stage to isolate the compound of formula (I), advantageously comprising the addition of alcoholic solvent as defined herein to wash the product. The reaction is sensitive to the water content and so the process preferably comprises the removal of water via azeotropic distillation. The water content can be controlled by azeotropic distillation, this has been found to be particularly effective when a co-base (such as potassium hydroxide) is used.
In a second aspect of the invention there is provided a process for preparing pinoxaden comprising a process as defined herein. Such a process may comprise the hydrolysis of a compound of formula (I) to form oxadiazepine (ODA). The ODA may be reacted with 2-(2,6-Diethyl-4- methylphenyl)malonamide in order to form a pinoxaden intermediate.
In a third aspect of the invention there is provided a compound of formula (I) produced by a process as defined in herein. Such a compound is preferably used in a process for the preparation of pinoxaden.
Unless otherwise stated all percentages are given as percentages by total weight and all embodiments and preferred features may be combined in any combination.
The invention is described by the following non-limiting Examples.
Examples
Example 1
Table 1 Procedure
DAH (40 g, 1 eq), n-Butanol (150.1 g), powdered K2CO3 (28.3 g, 0.6 eq), and 1,4- diazabicyclo[2.2.2]octane (0.74 g) were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (26 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux (over 60 minutes) with distillate collected. DCEE (73.2 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (130.6 g) were fed sub-surface separately via syringe pumps. DCEE and KOH solution were both fed over 4 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids (58.5 g) were removed via filtration at room temperature, which was followed by n-butanol wash (110 g). The combined filtrate and wash (366.2 g) gave a solution yield of 55.3%. Concentration under reduced pressure at 55-60 °C rendered a concentrate (98.3 g) containing about 37% of DAODA.
To crystallize DAODA, the concentrate was cooled slowly (over 60 min) to -10 °C with mixing. Product isolation through filtration, a cold n-butanol wash (12 g) at -5°C, and drying under vacuum at 60 °C afforded DAODA (29.0 g) in a 46% yield with a purity of 99.1%.
Example 2
Table 2 Procedure
DAH (40 g, 1 eq), n-Butanol (112.9 g), powdered K2CO3 (28.3 g, 0.6 eq), and 1,4- diazabicyclo[2.2.2]octane (0.74 g) were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (26 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux (over 60 minutes) with distillate collected. DCEE (73.2 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (130.6 g) were fed sub-surface separately via syringe pumps. DCEE and KOH solution were both fed over 4 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids (59.2 g) were removed via filtration at room temperature, which was followed by n-butanol wash (112 g). The combined filtrate and wash (342 g) gave a solution yield of 54.7%. Concentration under reduced pressure at 55-60 °C rendered a concentrate (88.5 g) containing about 37% of DAODA.
To crystallize DAODA, the concentrate was cooled slowly (over 60 min) to -10 °C with mixing. Product isolation through filtration, a cold n-butanol wash (12 g) at -5°C, and drying under vacuum at 60 °C afforded DAODA (28.5 g) in a 45% yield with a purity of 98.6%.
Example 3
Table 3 Procedure
DAH (30 g, 1 eq), n-Butanol (140.7 g), and powdered K2CO3 (28.3 g, 0.8 eq were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (19.6 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux (over 60 minutes) with distillate collected. Trimethylamine hydrochloride (1.19 g) in 1.0 mL of water was charged. DCEE (54.9 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (78.6 g) were fed sub-surface separately via syringe pumps. DCEE and KOH solution were both fed over 4 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids (48.0 g) were removed via filtration at room temperature, which was followed by n-butanol wash (110 g). The combined filtrate and wash (312.2 g) gave a solution yield of 51.0%.
Example 4
Table 4
Procedure
DAH (30 g, 1 eq), n-Butanol (140.7 g), powdered K2CO3 (28.3 g, 0.8 eq), and quinuclidine (0.55 g) were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (19.6 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux (over 60 minutes) with distillate collected. DCEE (54.9 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (78.4 g) were fed sub-surface separately via syringe pumps. DCEE and KOH solution were both fed over 4 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids (50.0 g) were removed via filtration at room temperature, which was followed by n-butanol wash (100 g). The combined filtrate and wash (314.4 g) gave a solution yield of 53.7%.
Example 5
Table 5
Procedure
DAH (30 g, 1 eq), n-Butanol (140.7 g), powdered K2CO3 (28.3 g, 0.8 eq), and tetrabutylphosphonium chloride (1.22 g) were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (19.6 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux (over 60 minutes) with distillate collected. DCEE (54.9 g, 1.5 eq) and a solution of 14.5 w/w% KOH in n-butanol (78.4 g) were fed sub-surface separately via syringe pumps. DCEE and KOH solution were both fed over 4 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period. After reaction completion, the inorganic solids (50.0 g) were removed via filtration at room temperature, which was followed by n-butanol wash (100 g). The combined filtrate and wash (292.8 g) gave a solution yield of 55.5%. Concentration under reduced pressure at 55-60 °C rendered a concentrate (55.8 g) containing about 43.5% of DAODA.
To crystallize DAODA, the concentrate was cooled slowly (over 60 min) to -10 °C with mixing. Product isolation through filtration, a cold n-butanol wash (12 g) at -5°C, and drying under vacuum at 60 °C afforded DAODA (20.6 g) in a 45% yield with a purity of 99 %.
Example 6
Table 6
Procedure
DAH (12 g 1 eq), n-butanol (56.3 g), powdered K2CO3 (11.4 g, 0.8 eq), and tetrabutylphosphonium chloride (0.6 g) were charged to an Easymax 102 reactor (150 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (7.9 g) was fed sub-surface over 15 minutes at room temperature. The suspension was heated to gentle reflux over 30 minutes. DCEE (24.9 g, 1.7 eq) and a solution of 14.5 w/w% KOH in n- butanol (31.4 g) were fed sub-surface separately via syringe pumps. DCEE was fed over 4 hours and KOH solution fed over 6 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 16-hour period. After reaction completion, the inorganic solids (25.4 g) were removed via filtration at room temperature followed by a n-butanol wash (30 g) at room temperature. The combined filtrate and n- butanol wash (163.5 g) gave a solution yield of 60.4%.
Example 7
Table 7
Procedure
DAH (39.6 g, 1 eq), n-Butanol (186.7 g), powdered K2CO3 (37.1 g, 0.8 eq), and tetrabutylphosphonium chloride (1.98 g) were charged to an Easymax 402 reactor (500 mL) equipped with overhead stirring, thermocouple, and reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w/w% KOH in n-butanol (26 g) was fed sub-surface over 30 minutes at room temperature. The suspension was heated to gentle reflux (over 30 minutes). DCEE (82.5 g, 1.7 eq) and a solution of 14.5 w/w% KOH in n-butanol (103.9 g) were fed sub-surface separately via syringe pumps. DCEE was fed over 4 hours and KOH solution fed over 6 hours. The rate of water/solvent removal was adjusted to match the feed rate of base. The reaction was sampled periodically over a 12-hour period. The GC chemical yield for DAODA was 55.3%.
After reaction completion, the inorganic solids (57.4 g) were removed via filtration at room temperature, which was followed by n-butanol wash (112 g). The combined filtrate (311.9 g) and wash (112 g) were concentrated under reduced pressure at 55-60 °C to render a concentrate (101.5 g) containing about 35% of DAODA. To crystallize DAODA, the concentrate was cooled slowly (over 60 min) to -10 °C with mixing. Product isolation through filtration, a cold n-butanol wash (20 g) at -5°C, and drying under vacuum at 60 °C afforded DAODA (30.0 g) in a 48.7% yield with a purity of 99%. The mother liquor (64 g) containing DAODA (5.1 g, 8.2% yield) and n-butanol wash (18.5 g) containing DAODA (0.7 g, 0.9% yield) were main sources of product loss.
Example 8
Table 8
Procedure
DAH (12 g, 1 eq), n-butanol (64 g), powdered KOH (6.4 g, 1 eq), powdered K2CO3 (21.4 g, 1.5 eq) and tetrabutylphosphonium hydroxide (1.5 g at 40%) were charged in sequence to an Easymax 102 reactor. The suspension was heated to a gentle reflux (over 15 minutes) and DCEE (22.4 g, 1.5 eq) was fed sub-surface over 4 hours via syringe pump while water was azeotropically removed from the system. Azeotropic distillation continued post feed until the reaction was completed. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids were removed via filtration at room temperature followed by a n-butanol wash (30 g) at room temperature. The combined filtrate (87 g) and wash (32 g) gave a solution yield of 55%. Example 9
Table 9
Procedure
DAH (52.9 g, 1 eq), n-butanol (192 g), tetrabutylphosphonium hydroxide (6.75 g at 40%), powdered K2CO3 (154.4 g, 2.5 eq) were charged to an Easymax 402 reactor. After the suspension was heated to gentle reflux over 15 minutes, DCEE (100.8 g, 1.5 eq) was fed sub-surface over 4 hours via syringe pump and the reaction was held at reflux for additional 8 hours.
After reaction completion, the inorganic solids were removed via filtration at 80 °C, which was followed by a hot n-butanol wash (150 g) at 80 °C. The combined filtrate (250 g) and wash (155.8g) were concentrated under reduced pressure at 60-65 °C to render a concentrate (92.6 g) containing about 55% of DAODA.
To crystallize DAODA, the concentrate was cooled slowly over 30 min to -5°C with mixing. Product isolation through filtration, a cold n-butanol wash (34 g) at -5°C, and drying under vacuum at 60°C afforded DAODA (37.5 g) in a 45% yield with a purity of 99%. The mother liquor (41.5 g), containing DAODA (6.1 g, 7.3% yield) and n-butanol wash (36.6 g) containing DAODA (3.4 g, 4% yield) were main sources of product loss. Example 10
Table 10 Procedure
DAH (18 g, 1 eq), n-butanol (55 g), crystallization mother liquor (15 g, from Example 9), powdered K2CO3 (53.6 g, 2.5 eq) were charged to an Easymax 102 reactor. After the suspension was heated to gentle reflux over 15 minutes, DCEE (33.6 g, 1.5 eq) was fed sub-surface over 4 hours via syringe pump while maintaining the reaction temperature at gentle reflux. The reaction was held under reflux for additional 8 hours. The GC chemical yield for DAODA was 56%.
To enable a better determination reaction performance, DAODA and DCEE in the crystallization mother liquor were subtracted from the direct quantification in the reaction mass.
Example 11
Table 11 Procedure
DAH (12 g, 1 eq), 2-methoxyethanol (58 g) and powdered K2CO3 (37.5 g, 2.55 eq) were charged in sequence to an Easymax 102 reactor. The suspension was heated to a gentle reflux over 15 minutes and DCEE (22.4 g, 1.5 eq) was fed sub-surface over 4 hours via syringe pump. The reaction was held under reflux for additional 8 hours. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids were removed via filtration at room temperature followed by a 2-methoxyethanol wash (25 g) at room temperature. The combined filtrate (95.4 g) gave a solution yield of 58%.
Example 12
Table 12
Procedure
DAH (18 g, 1 eq), 2-methoxyethanol (64 g) and powdered K2CO3 (42.0 g, 2.0 eq) were charged in sequence to an Easymax 102 reactor. The suspension was heated to a gentle reflux over 15 minutes and DCEE (33.6 g, 1.53 eq) was fed sub-surface over 4 hours via syringe pump. The reaction was held under reflux for additional 8 hours. The reaction was sampled periodically over a 12-hour period.
After reaction completion, the inorganic solids were removed via filtration at room temperature followed by a 2-methoxyethanol wash (40 g) at room temperature. The combined filtrate (149.9 g) gave a solution yield of 54.8%. It can therefore be seen that the claimed invention provides a reaction that is efficient, low-cost and safer than that known in the prior art.
The invention is defined by the claims.

Claims

Claims
1. A process for the preparation of a compound of formula (I):
R1-C(O)-NH-NH-C(O)-R2, with R3-CH2-CH2-O-CH2-CH2-R4, in the presence of an alcoholic solvent; wherein R1 and R2 are independently selected from straight or branched chain alkyl groups, or are bonded to form a 4, 5, or 6-membered heterocycle, and wherein R3 and R4 are independently selected from a halide or a sulphate.
2. A process according to claim 1, wherein R1 and R2 are i) methyl; or ii) are bonded to form a 5- membered heterocycle.
3. A process according to claim 1 or 2 wherein R3 and R4 are independently selected from methylsulfonyl, chlorine and/or bromine, preferably chlorine.
4. A process according to any of the preceding claims, wherein the alcoholic solvent is selected from a monohydric alcohol.
5. A process according to claim 4, wherein the solvent is selected from butanol, pentanol, or 2- methoxyethanol, preferably butanol.
6. A process according to any of the preceding claims, where the process is carried out in the presence of a phase-transfer catalyst (PTC).
7. A process according to claim 6, wherein the PTC is a nucleophilic catalyst, an ammonium catalyst or phosphonium catalyst, preferably a phosphonium catalyst.
8. A process according to claim 6 or 7, wherein the PTC is selected from 1,4- diazabicyclo[2.2.2]octane (DABCO), quinuclidine, Trimethylamine hydrochloride (TMA HCI), Tetrabutylphosphonium chloride (TBPCI), Tetrabutylphosphonium hydroxide (TBPOH) and Tributyltetradecylphosphonium chloride (TBTDPCI), preferably l,4-diazabicyclo[2.2.2]octane (DABCO).
9. A process according to any one of the preceding claims, where the process is carried out in the presence of a base.
10. A process according to claim 9, wherein the process is carried out in the presence of a base and a co-base.
11. A process according to claim 10, wherein the ratio of base to co-base is from 10:1 to 1:2, preferably from 5:1 to 1:1.
12. A process according to claims 9 to 11, wherein the base is selected from potassium carbonate, sodium carbonate and caesium carbonate, preferably potassium carbonate.
13. A process according to any of claims 10 to 12, wherein the co-base is selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide and caesium hydroxide, preferably potassium hydroxide
14. A process according to any of the preceding claims, wherein the reaction is carried out at the solvent reflux temperature, preferably from 110 to 125 °C.
15. A process according to any of the preceding claims comprising the removal of water via azeotropic distillation.
16. A process according to any of the preceding claims comprising a salt filtration step.
17. A process according to any of the preceding claims comprising a solvent distillation step, preferably only one solvent distillation step.
EP23719404.8A 2022-04-29 2023-04-20 Process for the preparation of [1,4,5]-oxadiazepine derivatives Pending EP4514783A1 (en)

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